We compared the in vitro and in vivo antibacterial activity of DRPM (formerly S4661), a new 1β-methylcarbapenem, with that of imipenem, panipenem, meropenem, biapenem, cefpirome, ceftazidime, and cefotaxime. DRPM was highly active against methicillin-susceptible staphylococci, penicillin-resistant S. pneumoniae and members of the family Enerobacteriaceae such as Escherichia coli and Enterobacter cloacae, with a MIC at which 90% of tested strains were inhibited (MIC₉₀) to 1μg/mL or less. Against imipenem-, ceftandime-, ciprofloxacin-, and gentamicin-resistant P. aeruginosa, DRPM was the most active among tested agents. The in vivo efficacy of DRPM against experimentally induced infection in mice caused by gram-positive and gramnegative bacteria, including penicillin-resistant Streptococcus pneumoniae and β-lactamase producing H. influenzae was similar to that of imipenem-cilastatin and meropenem-cilastatin. We conclude that DRPM is a promising new carbapenem for treating infections caused by gram-positive and negative bacteria, including penicillin-resistant S. pneumoniae and drug-resistant P. aeruginosa.

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The 90% minimum inhibitory concentrations (MIC₉₀) of the new 1-methylcarbapenem (DRPM)(Shionogi & Co., Ltd., Osaka) against clinical isolates of methicillin-susceptible Staphylococcus aureus (MSSA), methicillinresistant S. aureus (MRSA), Staphylococcus epidermidis, Staphylococcus haemolyticus, Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Moraxella catarrhalis, Haemophilus influenzae, Escherichia coli, Klebsiella pneumoniae, Proteus vulgaris, Morganella morganii, Enterobacter cloacae, Serratia marcescens, Pseudomonas aeruginosa were 0.1, 50, 25, 25, 0.2, ≤0.006, 6.25, >100, 0.025, 1.56, 0.1, 0.2, 6.25, 0.39, 1.56, 6.25, and 12.5μg/mL, DRPM showed well-balanced activity against both gram-positive and gam-negative bacteria.
The PBPs binding inhibitory pattern of DRPM against MSSA and MRSA was almost the same as that of imipenem. Below 4μg/mL concentrations, IPM manifested antibiotic activity against S. aureus, stronger than that of DRPM.
DRPM exbited higher binding affinity than imipenem to PBPs 3α, β of P. aeruginosa.

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In vitro activity of doripenem (DRPM), a 1β-methylcarbapenem, was compared to that of imipenem (IPM), meropenem (MEPM), biapenem (BIPM), and clindamycin (CLDM) against a variety of anaerobic bacteria and a small number of facultative anaerobic bacteria (68 reference strains and 477 clinical isolates).
DRPM had a broad spectrum against gram-positive and gram-negative reference strains of anaerobes, inhibiting many anaerobic bacterial strains at 0.78μg/mL, or less. The MIC of DRPM for most reference strains was distributed one-or two-fold higher than that of IPM and MEPM, and one-fold lower than BIPM. For clinical strains, DRPM also showed potent activity. The MIC_9O of DRPM for pigmented and non-pigmented Prevotella, Fusobacterium spp., anaerobic gram-positive cocci except for Peptostreptococcus anaerobius, and Clostriclium perfringens was 0.39μg/mL or less. For Bacteroides fragilis and Bacteroides thetaiotaomicron, DRPM showed good activity with a MIC90 of 0.78μg/mL. Stability of DRPM to 6 β-lactarnases with distinct substrate specificity extracted from 4 strains of B. fragilis and 2 strains of P. bivia was examined.
DRPM was hydrolyzed with metallo-β-lactamase but quite stable with other β-lactamases.

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In vitro and in vivo antibacterial activity of a new carbapenem antibiotic, doripenem (DRPM), was compared to that of imipenem (IPM), panipenem (PAPM), meropenem (MEPM), ceftazidime (CAZ), and cefpirome (CPR). DRPM showed a broad antibacterial spectrum against gram-positive bacteria such as Staphylococcus aureus and gram-negative bacteria including Pseudomonas aeruginosa. DRPM was 2-fold more active than MEPM against MSSA: MIC₉₀ of DRPM was 0.1μg/mL. Against Pseudomonas aeruginosa, DRPM was more potent than PAPM and CAZ and the same as IPM and MEPM, with MIC₉₀ of 3.13μg/mL. DRPM showed potent bactericidal activity against E. coll and Pseudomonas aeruginosa. Against Pseudomonas aeruginosa, DRPM showed a postantibiotic effect of 2.0h the same as IPM.
Therapeutic effects of DRPM were examined using an experimental infection model in mice. The efficacy of DRPM against systemic infection of Pseudomonas aeruginosa was equivalent to imipenem/cilastatin (IPM/CS) and meropenem/cilastatin (MEPM/CS) and was superior to CAZ. DRPM showed activity equal to IPM/CS and MEPM/CS in local K. pneumoniae and E. coli infection.

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We studied the in vitro antibacterial activity of doripenem (DRPM), a novel carbapenem, compared to imipenem, cefotaxime, ceftaziclime, and cefepime, against β-lactamase-producing bacteria. DRPM was active against class A strains, including extended-apectrum β-lactamase (ESBL), and against class C and D producers, but not against class B. DRPM activity against β-lactamase producers was 2-4 times stronger than that of IPM.

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We evaluated the in vitro postantibiotic effect and in vivo antimicrobial activity of doripenem (DRPM), a new carbapenem, against Staphylococcus aureus Smith, Klebsiella pneumoniae BK, Escherichia coli ATCC 25922, and Pseudomonas aeruginosa ATCC27853. PAE was determined by exposing the organism for 2 hours to DRPM, imipenem (IPM), panipenem (PAPM), and ceftazidime (CAZ) at concentrations of 4 times the MIC. For in vivo study, a neutropenic mouse-thigh infection model was used. Neutropenia was induced by injection with 150mg/kg of cyclophosphamide ip 4 days and 100mg/kg 1 day, before infection. The time when viable cell number return to the level at drug administration was defined as the effective regrowth time (ERT).
In vitro PAE of DRPM against S. aureus Smith, was 1.9h, IPM 1.6h, PAPM 1.8h, and CAZ 1.8h. Those against K pneumoniae BK were 0.3h, 0.5h, 0.4h, and 0.1h. Those against E. coli ATCC25922 were 0.5h, 0.6h, 0.6h and 0.4h. Those against P. aeruginosa ATCC27853 were 1.8h, 1.0h, 1.0h, and-0.3h.
In vivo ERT of DRPM with dose of 50mg/kg against S. aureus Smith was 7.8 h, IPM/cilastatin (CS) 12.3 h, and PAPW/betamipron (BP) 10.8h. Those of S-4661, IPM/CS, PAPM/BP, meropenem (MEPM) and CAZ against K. pneumoniae BK with dose of 50mg/kg were 5.0h, 5.5h, 4.3h, 5.0h, and 6.0h. Those against P. aeruginosa ATCC27853 with dose of 100mg/kg were 8.0h, 9.8h, 8.3h, 5.3h and 2.7h.
In vitro PAEs of DRPM against S. aureus Smith, K pneumoniae BK, and E. coli ATCC25922 were almost the same as other carbapenems and the longest of all against P. aeruginosa was ATCC27853. In vivo activity DRPM against K. pneumoniae BK and P. aeruginosaATCC27853 was almost the same as other carbapenems, but less potent against S. aureus Smith than IPM/CS and PAPM/BP.

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We studied the in vitro antibacterial activity of doripenem (DRPM), a novel parenteral carbapenem. DRPM showed a broad antibacterial spectrum against aerobic gram-positive and negative bacteria and anaerobic bacteria. In a susceptibility test for clinical strains isolated in 2002, MIC₉₀s of DRPM were≤0.016-1μg/mL for Streptococcus spp. and methicillin-susceptible strains of Staphylococcus spp., and 0.031-1μg/mL for Enterobacteriaceae, Moraxella catarrhalis, and Haemophilus influenzae, suggesting that DRPM has potent antibacterial activity. Of the 5 carbapenems tested, DRPM was most potent against aerobic gram-positive bacteria, following imipenem (IPM) and panipenem, and is most potent against aerobic gram-negative bacteria, following meropenem (MEPM). MIC₅₀, and MIC₉₀ of DRPM against Pseudomonas aeruginosa were 0.5 and 8μg/mL, indicating that DRPM has the most potent antipseudomonal activity among antibiotics tested. The antibacterial activity of DRPM was not affected by factors such as medium pH or inoculum size. Results from MBC determination and a time-kill study suggested that DRPM has strong bactericidal activity corresponding to its antibacterial activity. Although DRPM was hydrolyzed by metallo-β-lactamases as well as other carbapenems, it was stable to hydrolysis by class A, C, and D β-lactamases, including extended-spectrum β-lactamase. A study on the affinity of DRPM to penicillin-binding proteins as its mode of action suggested that DRPM probably exhibits antibacterial activity by inhibiting the activity of PBP1 for S. aureus, PBP2 and PBP3 for P. aeruginosa, and PBP2 for E. coli as well as MEPM. When subcultured repeatedly in media containing DRPM, MEPM, or IPM, bacterial strains of S. aureus, P. aeruginosa, and E. coil, showed decreased susceptibility to all of these antibiotics, and cross-resistance among tested carbapenems was observed.

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The in vivo antibacterial efficacy of doripenem (DRPM), a new parenteral carbapenem antibiotic, was compared to that of meropenem/cilastatin (MEPM/CS), imipenem/cilastatin (IPM/CS), ceftazidime (CAZ), and ampicillin (ABPC) against experimental infection in mice and rats.
Compared to a single administration of DRPM in mice, plasma concentration of DRPM with administration combined with CS (DRPM: CS=1:1) did not improve, but plasma concentration of DRPM in rats was improved by combination with CS. No difference was seen in pharmacokinetic properties of plasma among DRPM, MEPM/CS, and IPM/CS in mice and among DRPM/CS, MEPM/CS, and IPM/CS in rats.
Against murine systemic infection caused by gram-positive bacteria including penicillin-resistant Streptococcus pneumoniae (PRSP), DRPM exhibited good efficacy with ED₅₀ of 0.02-6.26mg/kg, superior to MEPM/CS, CAZ, and ABPC but inferior to IPM/CS. DRPM also showed potent efficacy (ED₅₀S: 0.04-2.49mg/kg) against gram-negative bacterial infection including CAZ-resistant Enterobacter cloacae and was more active than IPM/CS, but less active than MEPM/CS. In a mouse lung infection model caused by PRSP, DRPM caused significant reduction of viable cells in the lung at 3mg/kg or more, though ABPC was not effective at 10mg/kg. The therapeutic efficacy of DRPM was more active significantly than that of ABPC and CAZ and similar to that of MEPM/CS, but inferior to that of IPM/CS. In rat meningitis caused by PRSP, DRPM/CS caused significant reduction of viable cells in cerebrospinal fluid at 10mg/kg or more than. DRPM was more active than ABPC, CAZ, and MEPM/CS, but less active than IPM/CS. In a rat endocarditis model caused by Staphylococcus aureus, DRPM showed excellent efficacy with significant reduction of viable cells in the heart at 4mg/kg or more. Its efficacy was more potent than that of CAZ and MEPM/CS and was comparable to that of IPM/CS.
The in vivo antibacterial efficacy of DRPM against experimental systemic and local infection in mice and rats well reflected its in vitro activity and plasma concentrations in these animals.

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Doripenem (DRPM), a novel parenteral carbapenem antibiotic synthesized by Shionogi & Co., Ltd., has potent antibacterial activity and a well-balanced spectrum against aerobic Gram-positive and negative bacteria, and anaerobic bacteria. We evaluated its antipseudomonal activity.
DRPM exhibited potent activity with MIC₉₀ of 8μg/mL against clinical 71 strains of Pseudomonas aeruginosa isolated in 2002, 2-4 times more active than other carbapenems, meropenem (MEPM), imipenem (IPM), biapenem, and panipenem, and 2-8 times more potent than antipseudomonal antibiotics such as ceftazidime (CAZ), amikacin, and sulbactam/cefoperazone. DRPM was most active against CAZ-resistant and IPM-resistant P. aeruginosa compared to other carbapenems and CAZ.
DRPM as well as MEPM reduced antipseudomonal activity against mutant strains deficient in pore-forming protein OprD or overproduced efflux pump system, MexAB-OprM. Activity of DRPM against these strains was only 2-fold less active than their parent strains, whereas that of MEPM was 4-fold less active.
Against 20 clinical isolates of P. aeruginosa, the mean MBC of DRPM was 0.84μg/mL, which was lower than that of MEPM, IPM, and CAZ. MBC of DRPM against each strain was equal to or only twice larger than its MIC as well as other carbapenems, suggesting DRPM has strong bactericidal activity. In a time-kill study, DRPM exhibited time-dependent bactericidal activity, almost equal to that of MEPM and IPM.
DRPM showed post-antibiotic effect (PAE) against CAZ-susceptible P. aeruginosa in both in vitro and mouse lung infection models, while CAZ had no PAE. PAE of DRPM was similar to that of MEPM and IPM.
DRPM showed excellent therapeutic efficacy with ED₅₀ of 0.17-4.87mg/kg against systemic infection in both immunocompetent and neutropenic mice infected with P. aeruginosa including CAZ-resistant strains. DRPM was much more active than CAZ, more active than IPM/cilastatin (CS), and similar to MEPM/CS. DRPM also exhibited excellent efficacy against both mouse lung and urinary tract infection due to CAZ-resistant P. aeruginosa, equal to or more potent than IPM/CS and similar to MEPM/CS.
These results suggest that DRPM is clinically effective against P. aeruginosa infection.

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We evaluated the stability of doripenem, a novel carbapenem antibiotic, against human renal dehydropeptidase-I (DHP-I). Because imipenem, a carbapenem antibiotic, was reported to be easily hydrolyzed by human DHP-I, it is used in the clinic combined with DHP-I inhibitor cilastatin, so stability against human DHP-I plays an important roles in the human pharmacolcinetics of carbapenem antibiotics.
We evaluated stability against DHP-I using recombinant human renal DHP-I, purified by cilastatin-coupled affinity chromatography from COS-I cells producing DHP-I. Purified DHP-I was shown to form a broad single band in SDS-polyacrylamide gel electrophoresis, suggesting that it was produced as a glycosylated protein in COS-1 cells.
Stability was observed by determining the residual activity of the carbapenem antibiotics after incubation for 90 min in the presence of purified DHP-I. The residual activity of imipenem decreased with increasing activity of purified DHP-I. The residual activity of imipenem and meropenem after incubation with purified DHP-I was 20% and 80%, suggesting that meropenem, which is used without a DHP-I inhibitor in the clinic, is highly stable against DHP-I. Doripenem was as stable as meropenem under the same conditions, suggesting that doripenem and meropenem could be used without a DHP-I inhibitor in the clinic.

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We evaluated the bactericidal activity of doripenem, a novel carbapenem antibiotic, against clinical isolates by exposing strains for 24 h to doripenem concentrations likely to be produced in human plasma by intravenous injection in different dosage regimens. We observed the relationship between bactericidal activity and the percentage of time for which concentration was higher than the MIC for each isolate (T>MIC). Maximum bactericidal activity was observed when T>MIC exceeded 40%, and the number of viable cells at 24h incubation remained no more than the initial inoculum when T>MIC exceeded 25%.
Doripenem showed strong bactericidal activity against clinical isolates of Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa with a MIC of≤0.5μg/mL, under conditions simulating plasma concentrations when 250mg of doripenem was administered twice a day. Under these conditions, T>MIC exceeded 35% of the total exposure period. Bactericidal activity did not improve significantly when T>MIC duration was prolonged by simulating plasma concentration under the administration of 500 mg twice a day or 250mg three times a day. Against P. aeruginosa strains with MIC of≥2μg/mL, T>MIC was less than 25% under the conditions simulating serum concentration when 250mg of doripenem was administered twice a day. In these cases, bactericidal activity increased when T>MIC duration was prolonged by simulating serum concentration under the administration of 500mg twice a day or 250mg three times a day. The increase in the number of administrations per day caused more potent bactericidal activity than an increasein doses per administration because it prolonged T>MIC duration.
These results show a good relationship between the bactericidal activity of doripenem and the T>MIC duration, useful in determining the optimal dosing regimen.

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To evaluate the safety and pharmacokinetic profiles of doripenem (DRPM), a new carbapenem antibiotic for injection, we conducted a phase I study in 46 healthy male volunteers. DRPM was administered as follows: 1) a single infusion at a dose of 125-1, 000mg, 2) an infusion of 500mg twice a day (1, 000mg/day) for 6 days (11 repeated infusions), 3) an infusion of 1, 000mg twice a day (2, 000mg/day) for 6 days (11 repeated infusions), and 4) an infusion of 500mg 3 times a day (1, 500mg/day) for 1 day (3 repeated infusions).
In terms of safety, no abnormalities were found in the single-dose study. No abnormalities were found in electroencephalography or physical examination. In repeated dose studies, mild subjective symptoms/objective observations and slight changes in laboratory values were observed, although none were clinically relevant.
In the single-dose study, Cmax and AUC of DRPM increased in proportion to the dose, showing linearity between pharmacokinetic profiles and the DRPM dose. The plasma half-life of DRPM was approximately 1 hour at any dose. Within 24 hours of administration, approximately 75% of DRPM was excreted unchanged in urine. Results from the repeated-dose study showedthat DRPM pharmacokinetic profiles were not affected by a repeated dose. In addition, DRPM was found not to be accumulated.
The mean serum protein binding ratio was 5.4-15.2%. Intestinal flora was slightly affected by DRPM administration.
This study showed that DRPM administration is safe up to a dose of 1, 000mg, and pharmacokinetic profiles are not affected by a repeated dose, with no DRPM accumulation.

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We conducted a Phase I pharmacokinetic study of doripenem (DRPM), a new carbapenem antibiotic for injection, in 6 elderly male volunteers. DRPM was administered intravenously at a dose of 250mg (0.5-hour single infusion). We studied the effects of aging on pharmacokinetic profiles of DRPM by comparison with data in another study in healthy nonelderly male volunteers. We also assessed the safety of DRPM in the elderly.
Significant differences observed in plasma half-life, AUC, and systemic clearance between the elderly and nonelderly were not great. The change in mean plasma DRPM concentration showed no great differences between groups.
No adverse drug reactions were observed.
We concluded that aging has little effect on pharmacokinetic profiles of DRPM after a single dose at 250mg and thus the dosage and administration intended for the nonelderly also applies to the elderly people with no concern about DRPM safety.

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We compared pharmacokinetic profiles of doripenem (DRPM) in patients with renal dysfunction to those in healthy volunteers in a Phase I study.
Patients with renal dysfunction were divided into 3 groups based on creatinine clearance (Ccr): mild dysfunction with 50≤Ccr<70mL/min (Group I, n=4), moderate dysfunction with 30≤Ccr<50mL/min (Group II, n=6), and severe dysfunction with Ccr<30mL/min (Group III, n=2). Area under the blood concentration curve (AUC) in healthy volunteers after DRPM administration (250mg) was 20.26μg·h/mL, while AUCs in Groups I, II and III were 40.55μg·h/mL, 48.21μEg·h/mL and 64.31μg·h/mL. These results indicated that AUC increased with the severity of renal dysfunction. Half-lives were 0.90, 1.98, 2.16, and 3.56h in healthy volunteers, Group I, Group II, and Group III, and prolonged based on renal dysfunction severity.
Urinary excretion (0-24h) was 74.5%, 63.9%, 67.3%, and 58.2% in healthy volunteers, Group I, Group II, and Group III, decreasing based on renal dysfunction severity.
No adverse reactions were observed.
Our results suggest that the DRPM dosage and dosing interval should be determined carefully when in administration to patients with renal dysfunction.

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To determine the effects of probenecid on the renal excretion of doripenem (DRPM), a new carbapenem antibiotic for irkjection, we conducted an open-label, crossover (two-drug, two-period), single-dose study of DRPM in eight healthy male volunteers. DRPM was administered intravenously at a dose of 250mg with or without probenecid. Concentrations in plasma and urine were determined to evaluate differences in pharmacolcinetic profiles between two groups-one in which only DRPM was administered (DRPM group) and one in which DRPM was administered in combination with probenecid (DRPM/probenecid group).
Pharmacolcinetic parameters in the DRPM group were as follows: Cmax, 15.7±2.8μg/mL; AUC, 17.10±2.56 μg·h/mL; and half-life (t_1/2), 0.94±0.16h. Pharmacoldnetic parameters in the DRPM/probenecid group were as follows: Cmax, 18.1±1.4μg/mL; AUC, 29.86±2.10μgμh/mL; and t_1/2, 1.44±0.11h. The DRPM/probenecid group showed significant increases in Cmax and AUC (p=0.0091, p<0.0001), significant prolongation of t_1/2 (p=0.0002), and a significant decrease in the following parameters: systemic clearance, 8.41±0.58L/h versus 14.91±2.22L/h in the DRPM group (p<0.0001); renal clearance, 5.52±0.71L/h versus 12.00±2.21L/h in the DRPM group (p=0.0001); and cumulative urinary excretion (0-12h), 65.8±8.6% versus 80.4±8.0% in the DRPM group (p=0.0017).
These significant pharrnacokinetic differences suggest that DRPM is excreted both by glomerular filtration and tubular secretion.

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A multicenter prospective early phase II study was conducted at 41 sites in Japan in patients with internal and urologic infection to evaluate the dosage and administration of doripenem (DRPM), a new carbapenem antibiotic for injection, and to assess its safety and efficacy.
Subjects numbered 106, of whom 75 (internal medicine: 41, urology: 34) were evaluated for efficacy, 105 for safety in abnormal laboratory test findings, and 106 in abnormal symptoms. The usefulness of DRPM in 75 was evaluated and DRPM concentration in the sputum determined in 5.
DRPM was administered intravenously for 30 to 60 minutes at 125mg b.i.d., 250mg b.i.d., 250mg t. i. d., and 500mg b. i. d., with the following results:
Efficacy was 95.1%(39/41) in internal medicine patients and 97.1%(33/34) in urology patients, for an overall efficacy of 96.0%(72/75). Bacterial eradication was 86.4%(19/22) in internal medicine patients and 97.1%(33/34) in urology patients, for an overall bacterial eradication of 92.9%(52/56).
In safety, adverse drug reactions (symptoms) observed in 3 patients (3 events: tongue numbness, headache, and rash) were not serious and disappeared after completion of treatment. Adverse drug reactions (abnormal laboratory test findings) observed in 25 patients (45 events) included increased GPT (11 cases), GOT (6 cases), and eosinophilia (7 cases), all of which were slight and improved or returned to normal after completion of treatment. Overall safety was 98.1%(103/105).
Of the 75 patients evaluated for DRPM usefulness, usefulness rate 92.9%(39/42) in internal medicine patients and 93.9%(31/33) in urology patients, for an overall usefulness of 93.3%(70/75).
These results show that DRPM has the expected efficacy without adverse drug reactions that might raise clinical issues, so DRPM is expected to produce sufficient therapeutic effect in treating target infection.

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We conducted a late phase II study of doripenem (DRPM), a new carbapenem antibiotic for injection, in internal medicine.
1. Clinical efficacy
DRPM was administered at a dose of 250mg b.i.d., 250mg t.i.d., or 500mg b.i.d. for 3 to 14 days in patients with chronic respiratory tract infection, pneumonia, pulmonary suppuration, pyothorax, peritonsillar abscess, and cholecystitis. Overall efficacy was 87.6%(92/105). By disease, efficacy for patients with secondary infections associated with chronic respiratory disease was 93.1%(27/29) and for those with pneumonia, etc., 84.9%(62/73). A clinical efficacy evaluation of “effective” or “highly effective” was obtained in two patients with acute upper respiratory tract infection and in one with biliary tract infection.
2. Bacteriological effect
Bacterial eradication was observed in all 36 patients in whom changes in bacterial count from the baseline were investigated. Bacterial eradication was 100.0%.
3. Safety
Nonlaboratory adverse drug reactions occurred in two of 108 patients (1.9%) and laboratory adverse drug reactions in 32 of 106 patients (30.2%).
These results suggest that DRPM at a dose of 250mg b.i.d., 250mg t.i.d., or 500mg b.i.d. has sufficient therapeutic effect on patients with infection in internal medicine.

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A randomized, double-blind, dose-finding study on doripenem (DRPM), a new carbapenem antibiotic for injection, was conducted in patients with chronic respiratory tract infection to evaluate the safety and efficacy at the recommended dose of 250mg b.i.d. DRPM was also evaluated at a high dose of 500mg b.i.d. to show that the dose of 250mg b.i.d. is appropriate therapeutically.
1. Clinical efficacy
Of the 70 patients evaluated for efficacy, 36 took DRPM at the dose of 250mg b.i.d. Efficacy was 100.0%(36/36) and the 95% confidence interval was 90.3-100.0%. Based on clinical data from currently available carbapenem antibiotics, the expected efficacy of DRPM was calculated at 85% in patients with chronic respiratory tract infection. Actual efficacy was higher than expected efficacy. These results and the precision of efficacy analysis provided the rationale supporting the appropriateness of the dose (250mg b.i.d.) therapeutically for chronic respiratory tract infection. Efficacy at the high dose of 500mg b.i.d. was 88.2%(30/34) and no significant difference was seen between two groups.
2. Bacteriological effect
Bacteriological response was assessable in 36 of the 70 patients. Bacterial eradication was 94.1%(16/17) in the 250mg b.i.d. group and 89.5%(17/19) in the 500mg b.i.d. group with no significant difference seen between two groups.
3. Safety
The incidence of nonlaboratory adverse drug reactions was 2.6%(1/38) in the 250mg b.i.d. group and 2.9%(1/34) in the 500mg b.i.d. group. The incidence of laboratory adverse drug reactions was 28.9%(11/38) in the 250mg b.i.d. group and 23.5%(8/34) in the 500mg b.i.d. group with no significant difference between groups.
These results show that DRPM is sufficiently therapeutic and that the dose of 25mg b.i.d. is appropriate therapeutically for chronic respiratory tract infection.

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We evaluated the clinical efficacy and safety of doripenem (DRPM), a new carbapenem for injection, in respiratory infection in a randomized, double-blind, 2-group parallel-group, noninferiority comparative study with meropenem (MEPM). The dosage of DRPM was 250mg 2 times daily for 7 days (DRPM group) and that of MEPM 500mg 2 times daily for 7 days (MEPM). Results as follows:
1. Clinical efficacy
Subjects evaluated for clinical efficacy numbered 193. Clinical efficacy in the per-protocol-set was 92.7%(89/96) in the DRPM group 90.7%(88/97) in the MEPM group. DRPM thus demonstrated noninferiority to MEPM.
2. Bacteriological effect
About half of the subjects, or 91, evaluated for clinical efficacy were further evaluated for bacteriological effects. Eradication was 86.0%(37/43) in the DRPM group and 95.8%(46/48) in the MEPM group, no significant difference in eradication between groups.
3. Safety
Subjects were evaluated for nonlaboratory adverse drug reactions numbered 218. The incidence of nonlaboratory adverse drug reactions was 8.1%(9/111) in the DRPM group and 6.5%(7/107) in the MEPM group. Of these 217 were further evaluated for laboratory adverse drug reactions. The incidence of laboratory adverse drug reactions was 23.4%(26/111) in the DRPM group and 25.5%(27/106) in the MEPM group, indicating no significant difference in nonlaboratory or laboratory adverse drug reaction incidence.
DRPM (250mg 2 times daily for 7 days) is thus considered to have a novel therapeutic effect comparable to MEPM (500mg 2 times daily for 7 days).

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We conducted a therapeutic exploratory study to evaluate the efficacy and safety of doripenem (DRPM), a new carbapenem antibiotic for injection, in 18 patients aged 44 to 95 years, with hospital-acquired pneumonia. Of these 18 were evaluated for DRPM efficacy and divided by dose as follows: 10 at 500mg b.i.d., 3 at 500mg t.i.d., 1 at 1, 000mg b.i.d., and 1 at a starting dose of 500mg b.i.d. followed by 250mg b.i.d.(downward titration based on improvement in symptoms and patient age).
In all 1 of 18, DRPM was effective and clinical efficacy was evidenced as expected before the start of treatment.
For safety, nonlaboratory adverse drug reactions were observed in only 1 case, pseudomembranous colitis. Laboratory adverse drug reactions were observed in 5, most in abnormal liver function tests.
These results show that DRPM is useful for treating patients with hospital-acquired pneumonia.

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We conducted an open-label clinical study to determine the efficacy, safety, and dosage and administration of doripenem (DRPM), a new carbapenem antibiotic for injection, in patients with infection in urology. We also conducted a pharmacokinetic study to determine the distribution of DRPM in prostate tissue.
1. Efficacy
In the open-label clinical study, DRPM was evaluated in one patient with acute uncomplicated pyelonephritis, nine with complicated pyelonephritis, 11 with complicated cystitis, six with acute prostatitis, and five with epididymitis. DRPM was administered at a dose of 250mg, b.i.d., 250mg, t.i.d., or 500mg, b.i.d. for 3 to 14 days. Clinical efficacy judged by attending urologists was 84.4%(27/32), and for the dosage regimen used for the largest cohort of patients (250mg, b.i.d.) was 87.5%(21/24). Based on criteria of the Japanese UTI Committee, overall clinical efficacy for complicated urinary tract infection (pyelonephritis, cystitis) was 100.0%(16/16). Bacteriologically, eradication for 34 bacterial strains (13 gram-positive and 21 gram-negative) isolated prior to initiation of treatment was 97.1%.
2. Pharmacokinetics
In the pharmacokinetic study, DRPM was administered to prostatectomy patients at a single dose of 250mg or 500mg. Blood and prostate tissue samples were collected within 60 to 160 minutes of the start of administration. Prostate tissue concentration was 0.76-2.23μg/g in the 250mg group and 1.04-4.51μg/g in the 500mg group.
3. Safety
In the open-label clinical study, adverse drug reactions (symptoms) occurred in three of 40 patients (7.5%) and adverse drug reactions (abnormal laboratory findings) in eight of 39 (20.5%). In the pharmacokinetic study, adverse drug reactions (abnormal laboratory findings) occurred in oneof 12 patients (8.3%), with no adverse drug reactions (symptoms) reported in any of the 13 patients. No serious or clinically significant event was reported in either study.
These results suggest that DRPM is well distributed in prostate tissue and useful for urological infection treatment.

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We conducted a dose finding study of doripenem (DRPM), a new carbapenem antibiotic for irkjection, in patients with complicated urinary tract infections to evaluate the safety and efficacy of DRPM at the recommended dose of 250mg b.i.d.(250mg group). DRPM was also evaluated at a high dose of 500mg b.i.d.(500 mg group) to show that the dose of 250 mg b.i.d. is appropriate therapeutically.
Subjects were inpatients aged between 20 and 79 years shown to have pyuria of at least 5 WBCs/hpf and bacteriuria of at least 104CFU/mL. In patients with previous prostatic resection, an interval of more than 6 months after surgery was required for inclusion. Patients with indwelling catheters were excluded.
Overall efficacy (primary endpoint) was 97.4%(37/38) in the 250mg group and the 95% confidence interval was 86.2% to 99.9%. This efficacy was not below the minimuml 95% confidence interval (78.6%-98.3%) for expected efficacy (90%) and was still higher than expected efficacy. In the 500mg group, overall efficacy was 96.9%(31/32) and no significant difference was seen between groups.
For secondary endpoints, no significant difference was seen between groups: 1) effect on pyuria was 60.5% in the 250 mg group and 75.0% in the 500mg group, 2) effect on bacteriuria was 94.7% in the 250mg group and 84.4% in the 500mg group, 3) bacteriological response was 95.7% in the 250mg group and 97.7% in the 500mg group, and 4) clinical efficacy judged by attending urologists was 94.7% in the 250 mg group and 84.4% in the 500mg group. These results showed that efficacy at 250mg b.i.d. was equivalent to that at 500mg b.i.d.
For safety, the incidence of adverse drug reactions (symptoms) was 4.9% in the 250mg group and 2.9% in the 500mg group, respectively, and the incidence of adverse drug reactions (abnormal laboratory findings) 15.4% and 15.2%, with no significant difference seen between groups in either case.
Considering overall efficacy in the 250mg group (still higher than expected efficacy) and the precision of efficacy analysis, this study showed that DRPM at 250mg b.i.d. is appropriate as a therapeutic dose for patients with complicated urinary tract infection.

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We conducted a double-blind, controlled study to evaluate the safety and efficacy of doripenem (DRPM), a new carbapenem antibiotic for irjection, in patients with complicated urinary tract infection with meropenem (MEPM) set as the control drug. Subjects were in-patients aged 20 to 79 years shown to have pyuria of at least 5 WBCs/hpf and bacteriuria of at least 10⁴CFU/mL.
DRPM was administered at 250mg b.i.d. and MEPM at 500mg b.i.d. for 5 consecutive days. Based on the criteria proposed by the Japanese UTI Committee, DRPM and MEPM were evaluated for efficacy. Overall efficacy was 96.1%(73/76) in the DRPM group and 88.6%(70/79) in the MEPM group, demonstrating the non inferiority of DRPM to MEPM (Pn=0.0003). The bacteriological response was 95.9%(94/98) in the DRPM group and 96.2%(101/105) in the MEPM group, demonstrating the non inferiority of DRPM to MEPM (p=0.0036). For both gram-negative and gram-positive bacteria, the bacteriological response exceeded 95% in both groups. Clinical efficacy judged by attending urologists was 93.4%(71/76) in the DRPM group and 92.4%(73/79) in the MEPM group, demonstrating the non inferiority of DRPM to MEPM (Pn=0.0098).
For safety, the incidence of adverse drug reactions (symptoms) was 4.3%(4/92) in the DRPM group and 4.0%(4/101) in the MEPM group. The incidence of adverse drug reactions (abnormal laboratory findings) was 17.6%(16/91) in the DRPM group and 22.2%(22/99) in the MEPM group, with no significant difference between groups (Pe=1.0000, 0.4709).
These results show that DRPM at 250mg b.i.d. is useful for treating patients with complicated urinary tract infection, and equivalent to MEPM at 500mg b.i.d.

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We conducted pharrnacoldnelic studies to determine the concentrations of doripenem (DRPM), a new carbapenem antibiotic with broad antibacterial activity, in bile and gallbladder tissue (early phase II study) and in peritoneal fluid (phase III study). A late phase II study and a phase III study were also conducted in patients with surgical infection to evaluate the clinical efficacy of DRPM. Results are as follows:
1. Phamacokinenc profiles
A single 30-minute intravenous infusion of DRPM (250mg) was administered to ten patients scheduled to undergo cholecystectomy. DRPM concentration in bile was<0.16-15.4μg/mL and in gall bladder tissue <0.10-1.87μg/g
A single 30-minute intravenous infusion of DRPM (250mg) was administered to five patients who underwent abdominal surgery. Maximum plasma concentration was 10.5-24.4μg/mL and maximum peritoneal fluid concentration within the same period 2.36-5.17μg/mL.
2. Clinical efficacy and safety
safety Late phase II study (48patients): DRPM was administered at a dose of 250mg b. i. d., 250mg t. i. d., or 500mg b. i. d. for 3 to 14 days in 22 patients with postoperative infection, four with intraabdominal abscess, seven with peritonitis, four with liver abscess, six with cholecystitis, and five with cholangitis. Clinical efficacy was evaluated as “excellent” in 12, “good” in 31, “fair” in two, and “poor” in three, with efficacy of 89.6%(43/48). Bacterial eradication was 61.3%(19/31). Adverse drug reactions (symptoms) occurred in one of 48 (2.1%) and adverse drug reactions (abnormal laboratory findings) in seven of 46 (15.2%).
Phase Ea study (15patients): DRPM was administered at a dose of 250mg b. i. d., 250mg t. i. d., or 500mg b. i. d. for 4 to 14 days in seven patients with intraabdominal abscess, two with liver abscess, and six patients with cholecystitis. Clinical efficacy was evaluated as “excellent” in two and “good” in 13, with efficacy of 100%. Bacterial eradication was 54.5%(6/11). Adverse drug reactions (abnormal laboratory findings) occurred in four of 15 (26.7%), with no adverse drug reactions (symptoms) reported in any.
These results suggest that DRPM at a dose of 250mg b.i.d., 250mg t.i.d., or 500mg b.i.d. has a sufficient therapeutic effect on patients with surgical infection.

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We conducted basic and clinical studies on doripenem (DRPM), a new carbapenem antibiotic, in obstetrics and gynecology, with the following results.
1. Tissue penetration of genital organs
We studied DRPM concentration in internal genital organs and plasma after intravenous drip infusion of 250mg. DRPM concentration in the uterus was 0.33-9.89μg/g, in uterine appendages<0.20-10.6μg/g and in plasma 0.80-21.5μg/mL 40-360min after administration.
We studied DRPM concentration in retroperitoneal fluid and plasma after intravenous drip infusion of 250mg and 500mg. After a 30 min-infusion of DRPM (250mg and 500mg), the maximum concentration in retroperitoneal fluid was 3.15-9.82μg/mL (250mg infusion) and 9.53-13.9μg/mL (500mg infusion), and maximum plasma concentration (Cmax) at the end of infusion were 14.0-30.8μg/mL (250mg infusion) and 26.2-50.7μg/mL (500mg infusion).
2. Clinical evaluation
The 54 patients evaluable for clinical efficacy (intrauterine infection: 9; uterine adnexitis: 10; parametritis: 18; pelvic peritonitis: 14; and Douglas abscess: 3) had an efficacy of 88.9%(48/54). In microbiological efficacy, eradication was 80.0%(24/30). Adverse reactions observed in 2 patients consisted of drug eruption (1), tongue numbness, and hand-foot and general malaise (1), all of which were mild and disappeared during administration. Abnormal laboratory findings were observed in 22.0%of patients (11/50), most being slight elevations in liver function test such as GOT/UT, with no severe changes reported.
We concluded that DRPM is highly useful for treating gynecological infection.

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This study investigated antimicrobial susceptibility of doripenem (DRPM) against clinical isolates from obstetric and gynecologic infections, and the pharmacokinetics of DRPM in plasma, genital tissues, and exudate of the retroperitoneal space. We investigated the in vitro antibacterial activities of DRPM against 33 isolates of Streptococcus agalactiae, 31 of Escherichia coli, 21 of Finegoldia magna, 22 of Bacteroides fragilis, 28 of Prevotella bivia, using an agar dilution method. The MIC₅₀ and MIC₉₀ of DRPM for these strains were 0.25 and 1μg/mL. DRPM inhibited more than 90% of clinical isolates tested at the concentration of 1μg/mL. Also, 250milligram of DRPM was administered to 13 patients for exactly 30 minutes using an automatic drip infusion pump. The concentrations of DRPM in plasma, uterine endometrium, uterine myometrium, oviduct, and ovary were 0.11-18.4μg/mL, below 0.20-2.89, below 0.20-3.58, below 0.20-2.86, and below 0.20-4.52μg/g, respectively. The concentration in exudates of retroperitoneal space was 21.9μg/mL at 1 hour after the end of drip infusion. We could detect DRPM at the concentration of 0.69μg/mL even at 6 hours after drip infusion. DRPM therefore appears to show considerable potential with excellent antimicrobial activities and satisfactory tissue concentrations against the treatment of obstetric and gynecologic infections.

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We studied the distribution of doripenem (DRPM), a new carbapenem antibiotic for injection, in otolaryngologic tissue. To evaluate the efficacy and safety of DRPM, we also conducted an open-label clinical trial in patients with moderate to severe otitis media and peritonsillar abscess (including severe lacunar tonsillitis and peritonsillitis).
After an infusion of DRPM (250mg), the concentration in removed tissues (palatine tonsil and mucosa of middle ear), and the ratio to plasma concentration in the same period were 0.27-2.58μg/g and 6.1-33.2%(60-155minutes) in the palatine tonsil and 0.26-6.09μg/g and 2.7-42.9%(60-90 minutes) in the mucosa of the middle ear.
DRPM was administered at a dose of 250mg b. i. d., 250mg t. i. d., or 500mg b. i. d. for seven days. In otitis media, DRPM was “highly effective” in four patients and “effective” and “slightly effective” in one each. In peritonsillar abscess, DRPM was “highly effective” in four patients and “effective” in two patients. After DRPM infusion at the clinically recommended dose of 250mg, the concentration of DRPM in middle ear discharge and the ratio to plasma concentration in patients with otitis media were 0.32-0.72μg/mL and 4.2-18.8%(75-170minutes). Microbiological response was studied in nine patients-five with otitis media and four with peritonsillar abscess. We found it to be “eradicated” in four patients and “decreased” in one with otitis media; while in peritonsillar abscess, it was found to be “eradicated” in all the four. In safety, the incidence of adverse drug reactions (abnormal symptoms) was 6.7%(1/15) and that of adverse drug reactions (abnormal laboratory findings) 26.7%(4/15), none of which were serious.
These results suggest that DRPM is distributed well in otolaryngologic tissues and that DRPM administration at a dose of 250mg b. i. d. or t. i. d., or at a dose of 500mg b. i. d. is clinical by useful in otolaryngologic infection, with a wide antimicrobial spectrum and strong antimicrobial activity against gram-positive bacteria, gramnegative bacteria, and anaerobes.

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We conducted a multicenter clinical trial of doripenem (DRPM), a new carbapenem for injection, to examine its skin penetration and its clinical efficacy and safety in deep-seated skin infections. The concentration in skin tissue was 2.29-3.15μg/g and in plasma 6.48-18.1μg/mL 30-70minutes after a single i. v. injection of 250mg of DRPM. The ratio of skin concentration to plasma concentration was 15.7-36.9%.
The minimum inhibitory concentration (MIC) against two clinical isolates of Staphylococcus aureus was 0.05μg/mL.
DRPM was administered to 22 patients at a dose of 250 mg or 500 mg twice a day for 5-8 days.
Overall clinical efficacy was 100%(19/19). Cases by diagnosis consisted of 10 of cellulitis, 3 of erysipelas, 3 of lymphangitis, 1 of lymphadenitis and 2 of carbuncle. The bacteriological response was 85.0%(17/20).
Adverse reactions were observed in 13.6%(3/22) and abnormal laboratory findings in 36.4%(8/22). One developed pseudomembranous colitis after DRPM treatment followed by oral cefcapene pivoxil, and the causal relationship to the treatment with DRPM could not be ruled out. This adverse reaction disappeared rapidly after vancomycin administration.
These results suggest that DRPM is a useful antibacterial agent for deep-seated skin infection.

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We studied the distribution of doripenem (DRPM), a new carbapenem antibiotic for injection, in ocular tissue (aqueous humor) after DRPM infusion at a dosage of 250mg, and evaluated the efficacy and safety of DRPM administered in patients with corneal ulcer, orbital infection, and endophthalmitis after DRPM infusion at a dosage of 250mg, b. i. d. or t. i. d., or at 500mg, b. i. d.
DRPM concentration in the aqueous humor of those undergoing cataract surgery was 0.16-0.87mg/mL within 70-115 minutes of the start of infusion. Plasma concentration in the same period was 6.86-12.9μg/mL.
Of 15 patients evaluated for efficacy-corneal ulcer in 10, orbital infection in 4, and endophthalmitis in 1-DRPM was administered to 9 at a dose of 250mg b. i. d., to 3 at a dose of 250mg t. i. d., and to 3 at a dose of 500mg b. i. d. Clinical efficacy, the primary endpoint in this study, was 100.0%(15/15). Improvement on Day 2, a secondary endpoint, was 100%(15/15).
Bacteriological response was evaluated in 8 patients-corneal ulcer in 4, orbital infection in 3 and endophthalmitis in 1-1 of whom had α-Streptococcus infection, 3 Corynebacterium sp. infection, 2 P. aeruginosa infection, 1 P. acnes infection, and 1 S. aureus-P. intermedia mixed infection. Causative bacteria were eradicated in all 8 and no new strains appeared after DRPM administration.
All 15 were evaluated for safety, with the primary endpoint the absence or presence of adverse drug reactions (symptoms and laboratory findings) and the secondary endpoint overall safety. In 4, the 8 adverse events observed were mild to moderate and none was judged to be related to DRPM. In the abnormal laboratory findings reported in 5 (5 events), the causal relationship to DRPM could not be ruled out resulting in these 5 adverse events judged to be adverse drug reactions (abnormal laboratory findings), including an increase in ALT (3 events), an increase in AST (1), and an increase in γ-GPT (1). The incidence of adverse drug reactions was 33.3%(5/15) and all were mild and returned to normal. Many of these adverse drug reactions (abnormal laboratory findings) were similar to those of currently available carbapenem antibiotics. The overall safety of DRPM was 100.0%(15/15).

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We conducted clinical studies on doripenem (DRPM), a new injectable carbapenem antibiotic, of dentistry and oral surgery.
1. Clinical pharmacology study
The oral tissue concentration after single administration of DRPM in 10 cases was 0.34-2.19μg/g (70-105min) in the gingiva and 0.36-1.10μg/g (60-75min) in the cyst wall, so the tissue/plasma concentration ratio was 14.3-47.9% in the gingiva and 7.7-21.4% in the cyst wall.
2. Clinical study
1) Clinical efficacy
Patients with infection were administrated DRPM by intravenous infusion at 250mg b. i. d., 250mg t. i. d., or 500mg b. i. d. for 3-7days.
Clinical efficacy was excellent in 11 and good in 2, for an efficacy of 100.0% in osteitis, excellent in 6, and good in 5, and an efficacy of 100.0% in cellulitis.
2) Bacteriological effect
The bacteriological effect was eradication in 13, eradication of 100.0% in osteitis, eradication in 10, and persistence in 1, and eradication of 90.9% in cellulitis.
3) Safety
The incidence of nonlaboratory adverse drug reactions was 4.2%(1/24) and of laboratory adverse drug reactions 33.3%(8/24).
These results suggest that DRPM is useful, reflecting potent and well-balanced activity against aerobic and anaerobic gram-positive and gram-negative bacteria

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In this study, doripenem (DRPM) was administered to 11 patients (2: infective endocarditis, 9: sepsis). Of the 9 patients with sepsis, the primary focus was infection arising from urology in 7 and surgery in 2. DRPM was administered for 3-14 days for sepsis and 28 days for infective endocarditis. Based on the health of patients, the investigator or subinvestigator chose the number of doses per day considered appropriate. Clinical findings improved as expected and in all cases, DRPM was effective in treatment. The causative organism and identified in 5 cases: in sepsis, 1 case of Klebsiella pneumoniae and 2 cases of Escherichia coli, and in infective endocarditis, 1 each of Streptococcus sanguis and Streptococcus vestibularis. After completion of administration, all causative organisms had been eradicated.
For safety, nonlaboratory adverse drug reactions were observed in 2 patients: constipation in one and vomiting and diarrhea in the other. Laboratory adverse drug reactions were observed in 3, i.e., increased ALT (GPT) in 1, increased ALT (GPT) and γ-GTP in 1, and eosinophilia in 1.
These results show that DRPM is sufficiently therapeutic and that a dose of 500mg b. i. d. or t. i. d. is appropriate for sepsis and infective endocarditis.

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